We developed 9H1.B11, an anti-idiotypic anti-deep core/lipid A (DCLA), murine monoclonal antibody (mAb) that mimics the conserved DCLA region of lipopolysaccharide (LPS). It recognizes an epitope in the variable region of an DCLA mAb, binds to the murine macrophage cell surface, and inhibits LPS- induced macrophage cytokine secretion. We hypothesized that (1) active immunization with mAb 9H1.B11 would be associated with the development of anti-DCLA antibodies and (2) immunization would protect against subsequent gram negative bacterial challenge. Mice were immunized for 8 weeks before intraperitoneal (ip) challenge with Escherichia coli O111:B4 bacteria. Control animals were immunized with an irrelevant IgM antibody 8133 (negative control) or with LPS derived from Salmonella minnesota Re bacteria (positive control). Sera from immunized mice were collected, and titers against the core region of LPS (Re) and against LPS derived from the infecting E. coli strain were determined. Mice immunized with mAb 9H1.B11 developed measurable titers against S. minnesota Re LPS but not against the challenge strain of E. coli. However, immunization with 9H1.B11 on S. minnesota Re LPS protected against subsequent infection due to E. coli O111:B4 (100% survival). The group of mice immunized with IgM 8133 exhibited only 25% survival. The development of an anti-S. minnesota Re LPS titer after immunization with 9H1.B11 provides further evidence that a portion of 9H1.B11 mimics the conserved DCLA region of LPS. We believe that this approach holds considerable promise and plan further studies to define the mechanism by which protective capacity occurs.